Cyclosporin galenic forms

ABSTRACT

Pharmaceutical compositions comprising a cyclosporin as active ingredient, a fatty acid triglyceride, a glycerol fatty acid partial ester or propylene glycol or sorbitol complete or partial ester, preferably, and a tenside having an HLB of at least 10.

The present application is a continuation of U.S. Ser. No. 07/940,119,filed Sep. 3, 1992 now abandoned, which in turn is a continuation ofU.S. application Ser. No. 07/822,375, filed Jan. 17, 1992, nowabandoned, which in turn was a continuation of U.S. application Ser. No.07/481,082, filed Feb. 16, 1990 now abandoned, which in turn is acontinuation-in-part of U.S. application Ser. No. 07/462,373, filed Jan.9, 1990 now abandoned, which in turn was a continuation of U.S.application Ser. No. 07/373,736, filed Jun. 29, 1989 now abandoned,which in turn was a continuation of U.S. Ser. No. 07/193,986, filed May13, 1988 now abandoned, which in turn was a continuation of U.S.application Ser. No. 06/901,356, filed Aug. 28, 1986 now abandoned,which in turn was a continuation of U.S. application Ser. No.06/633,808, filed Jul. 24, 1984 now abandoned.

The present invention relates to novel galenic formulations, inparticular novel pharmaceutical compositions as well as novel oraldosage forms comprising a cyclosporin as active ingredient.

The cyclosporins comprise a class of structurally distinctive, cyclic,poly-N-methylated undecapeptides, commonly possessing pharmacological,in particular immunosuppressive, anti-inflammatory and/or anti-parasitic(in particular anti-protozoal, e.g. anti-malarial) activity. The firstof the cyclosporins to be isolated was the naturally occurring fungalmetabolite Ciclosporin or Cyclosporine, also known as cyclosporin A andcommercially available under the Registered Trade Mark SANDIMMUN® orSANDIMMUNE®. Ciclosporin is the cyclosporin of formula A. ##STR1##wherein --MeBmt-- represents theN-methyl-(4R)-4-but-2E-en-1-yl-4-methyl-(L)threonyl residue of formula B##STR2## in which --x--y-- is --CH═CH-- (trans).

As the parent of the class, Ciclosporin has so far received the mostattention. The primary area of clinical investigation for Ciclosporinhas been as an immunosuppressive agent, in particular in relation to itsapplication to recipients of organ transplants, e.g. heart, lung,combined heart-lung, liver, kidney, pancreatic, bone-marrow, skin andcorneal transplants and, in particular, allogenic organ transplants. Inthis field Ciclosporin has achieved a remarkable success and reputation.

At the same time, applicability of Ciclosporin to various autoimmunediseases and to inflammatory conditions, in particular inflammatoryconditions with an aetiology including an autoimmune component such asarthritis (for example rheumatoid arthritis, arthritis chronicaprogrediente and arthritis deformans) and rheumatic diseases, has beenintensive and reports and results in vitro, in animal models and inclinical trials are wide-spread in the literature. Specific auto-immunediseases for which Ciclosporin therapy has been proposed or appliedinclude, autoimmune hematological disorder (including e.g. hemolyticanaemia, aplastic anaemia, pure red cell anaemia and idiopathicthrombocytopaenia), systemic lupus erythematosus, polychondritis,sclerodoma, Wegener granulamatosis, dermatomyositis, chronic activehepatitis, myasthenia gravis, psoriasis, Steven-Johnson syndrome,idiopathic sprue, autoimmune inflammatory bowel disease (including e.g.ulcerative colitis and Crohn's disease) endocrine opthalmopathy, Gravesdisease, sarcoidosis, multiple sclerosis, primary billiary cirrhosis,juvenile diabetes (diabetes mellitus type I), uveitis (anterior andposterior), keratoconjunctivitis sicca and vernal keratoconjunctivitis,interstitial lung fibrosis, psoriatic arthritis and glomerulonephritis(with and without nephrotic syndrome, e.g. including idiopathicnephrotic syndrome or minimal change nephropathy).

Further areas of investigation have been potential applicability as ananti-parasitic, in particular anti-protozoal agent, with possible usessuggested including treatment of malaria, coccidiomycosis andschistosomiasis and, yet more recently, use in cancer therapy, e.g. asan agent for reversing or abrogating resistance to other anti-neoplasticor cytostatic therapy.

Since the original discovery of ciclosporin, a wide variety of naturallyoccurring cyclosporins have been isolated and identified and manyfurther non-natural cyclosporins have been prepared by total- orsemi-synthetic means or by the application of modified culturetechniques. The class comprised by the cyclosporins is thus nowsubstantial and includes, for example, the naturally occurringcyclosporins A through Z [c.f. Traber et al. 1, Helv. Chim. Acta. 60,1247-1255 (1977); Traber et al. 2, Helv. Chim. Acta. 65 no. 162,1655-1667 (1982); Kobel et al., Europ. J. Applied Microbiology andBiotechnology 14, 273-240 (1982); and yon Wartburg et al., Progress inAllergy, 38, 28-45 (1986)], as well as various non-natural cyclosporinderivatives and artificial or synthetic cyclosporins including the socalled dihydro-cyclosporins [in which the moiety --x--y-- of the--MeBmt-- residue (Formula B above) is saturated to give --x--y-- ═--CH₂ --CH₂ --]; derivatised cyclosporins (e.g. in which a furthersubstituent is introduced at the α-carbon atom of the sarcosyl residueat the 3-position of the cyclosporin molecule); cyclosporins in whichthe --MeBmt-- residue is present in isomeric form (e.g. in which theconfiguration across positions 6' and 7' of the --MeBmt-- residue is cisrather than trans); and cyclosporins wherein variant amino acids areincorporated at specific positions within the peptide sequence,employing e.g. the total synthetic method for the production ofcyclosporins developed by R. Wenger--see e.g. Traber 1, Traber 2 andKobel loc. cit.; U.S. Pat. Nos. 4,108,985, 4,210,581 and 4,220,641;European Patent Publication Nos. 0 034 567, 0 056 782 and 0 296 122;International Patent Publication No. WO 86/02080; Wenger 1, Transp.Proc. 15, Suppl. 1:2230 (1983); Wenget 2, Angew. Chem. Int. Ed., 24, 77(1985); and Wenger 3, Progress in the Chemistry of Organic NaturalProducts 50, 123 (1986).

The class comprised by the cyclosporins thus now includes, for example,[Thr]² -, [Val]² -, [Nva]² - and [Nva]² -[Nva]⁵ -Ciclosporin (also knownas cyclosporins C,D, G and M respectively), [3'-O-acyl-MeBmt]¹-Ciclosporin (also known as cyclosporin A acetate), [Dihydro-MeBmt]¹-[Val]² -Ciclosporin (also known as dihydro-cyclosporin D),[3'-Desoxy-3'-oxo-MeBmt]¹ [Val]² - and -[Nva]² -Ciclosporin,[(D)Fluoromethyl-Sar]³ -Ciclosporin, [(D)Ser]⁸ -Ciclosporin, [MeIle]¹¹-Ciclosporin, [(D)MeVal]¹¹ -Ciclosporin (also known as cyclosporin H),[MeAla]⁶ -Ciclosporin, [(D)Pro]³ -Ciclosporin and so on.

[In accordance with now conventional nomenclature for cyclosporins,these are defined by reference to the structure of Ciclosporin (i.e.Cyclosporin A). This is done by first indicating the amino acid residuespresent which differ from those present in Ciclosporin (e.g. "[(D)Pro]³" to indicate that the cyclosporin in question has a --(D)Pro-- ratherthan --Sar-- residue at the 3-position) and then applying the term"Ciclosporin" to characterise remaining residues which are identical tothose present in Ciclosporin. Individual residues are numbered startingwith the residue --MeBmt--, --dihydro--MeBmt-- or its equivalent inposition 1.]

Very many of these further cyclosporins exhibit comparablepharmaceutical utility to Ciclosporin or more specific utility, forexample activity particularly in reversing tumor resistance tocytostatic therapy, and proposals for their application as therapeuticagents abound in the literature.

Despite the major contribution which Ciclosporin has made, in particularto the areas of organ transplant and the therapy of autoimmune diseases,difficulties encountered in providing more effective and convenientmeans of administration (e.g. galenic formulations, for example oraldosage forms, which are both convenient for the patient as well asproviding appropriate bio-availability and allowing dosaging at anappropriate and controlled dosage rate) as well as the reportedoccurrence of undesirable side reactions, in particular nephrotoxicreaction, have been obvious serious impediments to its wider use orapplication.

The cyclosporins are characteristically highly hydrophobic and readilyprecipitate in the presence of even very minor amounts of water, e.g. oncontact with the body (e.g. stomach) fluids. It is accordingly extremelydifficult to provide, e.g. oral formulations which are acceptable to thepatient in terms of form and taste, which are stable on storage andwhich can be administered on a regular basis to provide suitable andcontrollable patient dosaging.

Proposed liquid formulations, e.g. for oral administration ofcyclosporins, have hitherto been based on the use of oils in conjunctionwith solvent systems comprising, e.g. ethanol and LABRAFIL andequivalent excipients as carrier media. Thus the commercially availableCiclosporin drink-solution employs ethanol and olive oil or corn-oil ascarrier medium in conjunction with a LABRAFIL as co-solvent--see e.g.U.S. Pat. No. 4,388,307. Use of the drink-solution and similarcompositions as proposed in the art is however accompanied by a varietyof difficulties.

First the palatability of the known oil based systems has provedproblematic. The taste of the known drink-solution is, in particular,unpleasant and admixture with an appropriate flavoured drink, forexample chocolate drink preparation, at high dilution immediately priorto ingestion has generally been practiced in order to make regulartherapy at all acceptable. Adoption of oil based systems hitherto hasalso required the use of high ethanol concentrations to maintainsolubility. Use of ethanol is in itself inherently undesirable, inparticular where administration to children is foreseen. In addition,evaporation of the ethanol, e.g. from encapsulated forms (adopted, inlarge part, to meet problems of palatibility as discussed above), orother forms (e.g. when opened) results in development of a precipitate.Where such compositions are presented in e.g. soft gelatin encapsulatedform, this particular difficulty necessitates packaging of theencapsulated product in an air-tight compartment, for example anair-tight blister or aluminium-foil blister package or container. Thisin turn renders the product both bulky and more expensive to produce.The storage characteristics of such formulations are thus far fromideal.

Use of such dosage forms is also characterised by extreme variation inrequired patient dosaging. In order to achieve effectiveimmunosuppressive therapy, cyclosporin blood or blood serum levels haveto be maintained within in a specified range. This range in turn canvary, depending on the particular condition being treated, e.g. whethertherapy is to prevent transplant rejection or for the control of anautoimmune disease or condition, and on whether or not alternativeimmunosuppressive therapy is employed concomitantly with cyclosporintherapy. Experience shows however that, e.g. employing the availableCiclosporin drink solution, daily dosages needed to achieve requiredblood serum levels vary considerably from individual to individual andeven for a single individual at different times. For this reason it isnecessary to monitor blood/blood-serum levels of patients receivingCiclosporin therapy at regular and frequent intervals in order that thedaily dosage taken may be adjusted to maintain blood/blood-serum levelswithin the required range. Monitoring of blood/blood-serum levels, whichis generally performed by RIA or equivalent immunoassay technique, e.g.employing monoclonal antibody based technology, has to be carried outfor each patient receiving Ciclosporin therapy on a regular basis. Thisis inevitably time consuming and inconvenient and adds substantially tothe overall cost of therapy.

It is also the case that blood/blood-serum cyclosporin levels achievedusing available dosage systems exhibit extreme variation between peakand trough levels. That is, for each patient, effective cyclosporinlevels in the blood vary widely between administration of individualdosages. This variation in patient response has been found to beattributable to a significant extent to variation in the availability ofnaturally occurring surfactant components, e.g. bile acids and salts,within the gastro-intestinal tract of the subject treated. For galenicformulations for cyclosporins hitherto known in the art, the presence ofsuch natural surfactants in sufficient quantity is required ifsatisfactory resorption is to be achieved. However the availability ofsuch surfactants in the gastro-intestinal tract inevitably varies fromsubject to subject and in individual subjects with time.

Apart from the unsatisfactory nature of such inconsistancy in therapy,this also means that individual patients must be monitored on eachoccasion within a relatively narrow time-window, to ensure, e.g. that apeak level is not inadvertantly recorded as a high response to dosage.

Beyond all these very evident practical difficulties lies the occurrenceof undesirable side reactions already alluded to, observed employingavailable oral dosage forms.

Several proposals to meet these various problems have been suggested inthe art, including both solid and liquid oral dosage forms. Anoverriding difficulty has however remained the inherent insolubility ofthe cyclosporins, e.g. Ciclosporin, in aqueous media and hence provisionof a dosage form which can contain cyclosporins in sufficiently highconcentration to permit convenient use and yet meet the requiredcriteria in terms of bioavailability, e.g. enabling effective resorptionfrom the stomach or gut lumen and achievement of consistent andappropriately high blood/blood-serum levels.

As already noted, current commercial oral dosage forms for Ciclosporinare disclosed and claimed, e.g. in U.S. Pat. No. 4,388,307. The earlyphase of this development is reflected in Swiss patent application no.8634/78-8 which serves as a priority document to this patent. Thisapplication is directed to galenic formulations comprising Ciclosporinas the active ingredient together with a carrier medium comprising anyone or more of the following components:

i) sesame oil;

ii) a non-ionic tenside, e.g. TWEEN 80, CREMOPHORE EL, 40 or 60 orlecithins;

iii) a trans-esterified non-ionic triglyceride, e.g. LABRAFIL;

iv) mixtures of a lecithin (e.g. EPIKURON), ingredients (iii) andethyloleate;

v) neutral oils, e.g. saturated C₈₋₁₂ triglycerides such as MIGLYOL 812;and

vi) mono- and/or di-glycerides such as glycerol monooleate, glycerolmonostearate and glycerol distearate.

In the text and examples: (i) is described for use alone, for oral orparenteral administration; (ii) are described for use in combinationwith ethanol for oral or parenteral administration and in combinationwith components (v) for parenteral application; (iii) are described foruse alone and in conjunction with a vegetable oil and, additionally,ethanol for oral or parenteral administration; (iv) is described interms of the defined combination with possible further additives, forexample conserving agents, for oral administration; (v) are describedfor use in combination with solvents such as ethanol, benzoic acidbenzyl ester, 1,2-butyleneglycol-1-methyl ether and components (iii)(LABRAFIL) as well as in combination with components (ii) as set forthabove, in particular for parenteral administration; and (vi) aredescribed for use alone or in combination with thickening agents such asaerosil or cellulose for oral administration in encapsulated or pelletedform. No specific proposal is made for the combination of components(vi) [mono-/di-glycerides] with any other component (i) to (v), or viceversa.

In the patent application which matured as U.S. Pat. No. 4,388,307, thefocus of development set out in the above Swiss application isconcentrated on compositions comprising cyclosporins as activeingredient, together with a carrier medium comprising one or more ofcomponents (iii) [LABRAFIL etc.], (v) [neutral oils] and (vi)[mono-/di-glycerides, in particular stearic or oleic mono/di-glycerides,especially glycerol monooleate]. In relation to oral dosage forms, useof co-solvents, ethanol and vegetable oils such as olive oil and cornoil, is preferred. Components (v) are specifically indicated aspreferred in relation to parenteral, dosage forms. Components (vi) areproposed for use with lecithins, optionally together with components(iii) in orally administered aqueous or aqueous/ethanolic emulsions.

Belgian Patent no. 895 724, which relates primarily to the use of[dihydro-MeBmt]¹ -[Val]² -Ciclosporin (or dihydro-cyclosporin D) in thetreatment of multiple sclerosis, also describes two oral formulationssuitable for the administration of this particular compound. Both ofthese are based on the commercial Ciclosporin (SANDIMMUN CYCLOSPORIN A)drink-solution, with adaptation to suit the particular cyclosporinactive ingredient. The first comprises 5-10% [Dihydro-MeBmt]¹ -[Val]²-Ciclosporin, 10-12% ethanol, 30-40% MAISINE, ca. 4% CREMOPHORE and51-30% LABRAFIL (i.e. to 100%). This corresponds to the composition ofthe SANDIMMUN CYCLOSPORIN A drink-solution, but with the replacement ofthe natural vegetable oil component with MAISINE and introduction of aminor pecentage of the tenside CREMOPHORE. MAISINE is atrans-esterification product of corn oil with glycerol, the more precisecomposition of which is described hereinafter. It comprises corn oilderived triglycerides and mono-/di-glycerides in the ratio ca. 1:8 p.p.w(tri-:mono-/di-glycerides). The ratio of cyclosporin: tenside in thedisclosed composition is ca. 1:0.4-0.8, and the ratio of cyclosporin:triglycerides: mono-/di-glycerides is ca. 1:0.4-0.9:2.6-7.1. No proposalis made for possible increase in the tenside component nor for any meansof avoiding the use of LABRAFIL or ethanol components as co-solvents.

The second disclosed composition comprises: 15-25% [Dihydro-MeBmt]¹-[Val]² -Ciclosporin, 2-5% ethanol, 40-60% MAISINE and 10-40% IMWITOR742, a coconut oil mono-glyceride product comprising >45% monoglycerideswith additional di- and tri-glyceride components. Again, the use ofethanol is not avoided and no proposal is made for incorporation of anytenside component.

An Austrailian patent application discloses the use of tensidesbelonging to the group comprising polyethoxylated castor oils,polyethoxylated hydrogenated castor oils and polyethoxylated fatty acidsderived from castor oil or hydrogenated castor oil, such as CREMOPHORE,MYRJ, and NIKKOL HCO-60 as solubilizers for the incorporation ofdifficultly soluble pharmaceutical agents into controlled releasesystems, such as hydrophilic gel systems. Difficultly solublepharmaceuticals recited include Ciclosporine, though no example of theapplication of the system to cyclosporins is given. Nor is there anyteaching for the use of the recited solubilizers/tensides in conjunctionwith simple fatty acid mono-, di- or tri-glycerides.

In accordance with the present invention, it has now surprisingly beenfound that pharmaceutical compositions comprising cyclosporins, inparticular Ciclosporin, as active ingredient, which meet orsubstantially reduce difficulties in dosaging and patient acceptabilityhitherto encountered in the art, e.g. as discussed above, can beachieved by the use of carrier systems comprising fatty acidtri-glycerides and mono-/di-glycerides, suitably in combination orconjunction with a hydrophilic tenside. In particular, it has been foundthat, employing the defined carrier systems, it is possible to obtainoil-based compositions, which are not aqueous emulsions, and which donot require the presence of additional solvents, co-solvents orsolubilizers, for example ethanol or LABRAFIL or the like, and whichexhibit high stability as well as improved bioavailabilitycharacteristics as compared with known cyclosporin/fatty acidtriglyceride/solvent/co-solvent systems, for example, the knownSANDIMMUN CYCLOSPORIN A drink-solution. In a specific aspect the presentinvention provides for oil-based pharmaceutical compositions, inparticular oil-based pharmaceutical compositions other than aqueousemulsions, which are free or substantially free of ethanol.

In particular, it has been found that compositions in accordance withthe present invention enable effective cyclosporin dosaging withconcomitant enhancement of resorption/bioavailability levels, and/orreduced variability in resorption/bioavailability levels, achieved bothfor individual patients receiving cyclosporin therapy as well as betweenindividuals. In particular it has surprisingly been found that thecompositions of the invention enable resorption of cyclosporins in amanner that is independent, or of substantially reduced dependency, uponthe relative availability of natural surfactant materials, e.g. bileacids or salts, in the gastro-intestinal tract of the subject treated.By application of the teachings of the present invention, cyclosporindosage forms are obtained providing reduced variability in achievedcyclosporin blood/blood serum levels between dosages as well as betweenindividuals. The invention thus enables reduction of cyclosporin dosagelevels required to achieve effective therapy. In addition, it permitscloser standardisation as well as optimisation of on-going daily dosagerequirements for individual subjects receiving cyclosporin therapy aswell as for groups of patients undergoing equivalent therapy.

By closer standardisation of individual patient dosaging rate andblood/blood-serum level response, as well as dosaging and responseparameters for patient groups, monitoring requirements may be reduced,thus substantially reducing the cost of therapy.

By reduction of required cyclosporin dosaging/standardisation ofachieved bio-availability characteristics, the present invention alsoprovides a means which may permit reduction in the occurrence ofundesirable side-effects, in particular nephrotoxic reaction, inpatients undergoing cyclosporin therapy.

In addition, the compositions of the invention exhibit improvedstability on storage as compared with compositions based on the use ofethanol or equivalent alkanols and are, in particular, better adapted,e.g. for presentation in capsule, e.g. hard or soft gelatin capsule,form. Compositions in accordance with the findings of the presentinvention which are free or substantially free of ethanol have theparticular advantage of eliminating or substantially reducing packagingdifficulties, for example as hereinbefore discussed, e.g. in relation tothe packaging of soft gelatin encapsulated forms.

In accordance with the present invention there is provided, in itsbroadest aspect:

A. A pharmaceutical composition comprising:

a) a cyclosporin as active ingredient in a carrier medium comprising

b) a fatty acid triglyceride and

c) a glycerol fatty acid partial ester or propylene glycol (e.g.1,2-propylene glycol) or sorbitol complete or partial ester.

The term "pharmaceutical composition" as used throughout the presentspecification and accompanying claims is to be understood as definingcompositions of which the individual components or ingredients arethemselves pharmaceutically acceptable, e.g. where oral administrationis foreseen, acceptable for oral use or, where topical administration isforeseen, topically acceptable.

Component (a) in the compositions of the invention may be anytherapeutically applicable cyclosporin, e.g. as hereinbefore indicated.The preferred component (a) in the compositions of the invention isCiclosporin. A further preferred component (a) in the compositions ofthe invention is [Nva]² -Ciclosporin, also known as cyclosporin G.

Components (b) and (c) in the compositions of the invention may compriseor consist or consist essentially of the individual components (b) and(c) of a single ingredient, e.g. single material or product. Suitableproducts of this type include, in particular, transesterificationproducts of vegetable oils with glycerol, propylene glycol (e.g.1,2-propylene glycol) or sorbitol.

Accordingly, in one particular series of embodiments the presentinvention provides:

B¹ A pharmaceutical composition comprising:

a) a cyclosporin as active ingredient in a carrier medium comprising

b+c) a transesterification product of a vegetable oil with glycerol,propylene glycol or sorbitol;

B² A pharmaceutical composition comprising:

a) cyclosporin as active ingredient in a carrier medium comprising

b+c) a transesterification product of a vegetable oil with glycerol orsorbitol; and

B³ A pharmaceutical composition comprising:

a) a cyclosporin as active ingredient in a carrier medium comprising

b+c) a transesterification product of a natural vegetable oil andglycerol or sorbitol.

Ingredients (b+c) for use in compositions of the invention as definedunder B¹ to B³ above include trans-esterification products of anyappropriate natural (e.g. non-hydrogenated) or hydrogenated vegetableoil. Suitably they are, as specifically in the case of definition B³,trans-esterification products of natural vegetable oils, for example,almond oil, ground-nut oil, olive oil, palm oil or, preferably, cornoil.

Such trans-esterification products [ingredients (b+c)] are generallyobtained by heating of the vegetable oil, e.g. corn oil, with glycerol,propylene glycol or sorbitol [e.g. glycerol or sorbitol], at hightemperature under an inert atmosphere with continuous agitation, e.g. ina stainless steel reactor, to effect trans-esterification, e.g.glycerolysis, glycolysis or sorbitolysis. Ingredients (b+c) thuscomprise mixtures of mono-, di- and tri-glycerides (i.e. glycerol mono-,di- and tri-esters) with generally minor amounts of free glycerol.

Where ingredients (b+c) for use in the invention are obtained bytrans-esterification of a vegetable oil with sorbitol they will alsocontain free sorbitol as well as sorbitol mono-, di-, tri- andtetra-esters.

Where ingredients (b+c) for use in the invention are obtained bytrans-esterification of a vegetable oil with propylene glycol they willalso contain free propylene glycol (e.g. 1,2-propylene glycol) as wellas propylene glycol mono- and di-esters.

In general free sorbitol/free propylene glycol will be present inrelatively minor amounts, the recited mono-, di-, as well as tri- andtetra-esters when sorbitol is employed, in relatively substantialamounts.

The amount of triglyceride present in ingredients (b+c) for use in theinvention will preferably be substantial, e.g. in excess of 5%, suitablyfrom 7.5 to 12% by weight based on the total weight of the individualcomponents (b) and (c) in said ingredient.

The amount of free glycerol plus any free propylene glycol or sorbitolpresent in ingredients (b+c) for use in the invention is preferably lessthan 10%, more preferably less than 5%, most preferably 1 to 2% or lessbased on the total weight of said ingredient. The amount ofmono-glyceride present in ingredients (b+c) for use in the invention ispreferably ca. 25 to 50%, more preferably ca. 30 to 45%, by weight basedon the total weight of said ingredient.

When (b+c) is a trans-esterification product of a vegetable oil, e.g.corn oil, and glycerol, the amount of free glycerol present in saidproduct is preferably less than 10%, more preferably less than 5%, mostpreferably less than ca. 4% by weight. The amount of mono-glyceridepresent is preferably about 30 or 35 to 50% by weight, more preferablyabout 35 or 40 to 45% by weight. The amount of di-glyceride present ispreferably less than about 60%, suitably less than 40%, by weight. Theamount of tri-glyceride present is preferably up to about 14% by weight,e.g. ca. 7.5 to 12 or 14% by weight (all percentages being based on thetotal weight of said product). The ratio of the components (b):(c) inthe defined trans-esterification products is thus suitably of the orderof ca. 1:8 to ca. 1:9 p.p.w.

When (b+c) is a trans-esterification product of a vegetable oil, e.g.corn oil, and sorbitol, the amount of free glycerol plus free sorbitolpresent in said product is preferably less than 5% by weight, morepreferably ca. 1 to 2% by weight. The amount of mono-glyceride presentis preferably ca. 30 to 40% by weight, more preferably ca. 35% by weight(all percentages being based on the total weight of said product).

Particularly suitable trans-esterification products [ingredients (b+c)]for use in accordance with the present invention aretrans-esterification products of corn oil and glycerol, for example ascommercially available under the trade name MAISINE. Such products arecomprised predominantly of linoleic and oleic acid mono-, di- andtri-glycerides together with minor amounts of palmitic and stearic acidmono-, di- and tri-glycerides (corn oil itself being comprised of ca.56% by weight linoleic acid, 30% oleic acid, ca. 10% palmitic and ca. 3%stearic acid constituents). Physical characteristics for MAISINE[available from the company Etablissements Gattcrosse, of 36, Chemin deGenas, P.O.Box 603, 69804 Saint-Priest, Cedex (France)] are: approximatecomposition

free glycerol--10% max. (typically 3.9-4.9% or, in more recent batches,ca. 0.2%)

monoglycerides--ca. 40% (typically 41-44.1% or, in more recent batches,ca. 38%)

diglycerides--ca. 40% (or, in more recent batches, ca. 46%)

triglycerides--ca. 10% (or, in more recent batches, ca. 12%)

free oleic acid content--ca. 1%

Further physical characteristics for MAISINE are: acid value=max. ca. 2,iodine no.=ca. 85-105, saponification no.=ca. 150-175, mineral acidcontent=0.

The fatty acid content for MAISINE is typically: palmitic acid--ca. 11%;stearic acid--ca. 2.5%; oleic acid--ca. 29%; linoleic acid--ca. 56%;others--ca. 1.5%.

Further trans-esterification products [ingredients (b+c)] suitable foruse in accordance with the present invention are trans-esterificationproducts of corn oil and sorbitol, for example as commercially availableunder the trade name SORBITO GLYCERIDE from the company EtablissementsGattefosse, for example SORBITO GLYCERIDE WL 713, which has thefollowing approximate composition:

    ______________________________________                                        Product: trans-esterification product of ca. 2 Mol corn oil and               ca. 1 Mol sorbitol:                                                           ______________________________________                                        Approximate composition                                                        free glycerol                                                                                ca. 1 to 2%                                                   free sorbitol                                                                 monoglycerides  ca. 35%                                                       plus: di- and tri-glycerides and sorbitol mono-, di-, tri- and                tetra-esters.                                                                 ______________________________________                                         Color (Echelle Garner) = <8. Highly soluble in ethanol and                    chloroform/slightly soluble in ethylether/insoluble in H.sub.2 O. Acid no     = <1; saponification no. = ca. 160-185; iodine no. = ca. 110-140.        

The carrier medium of compositions in accordance with B¹ to B³ above maycomprise (b+c) alone or together with one or more additional excipients,additives or other ingredients as known in the art, for examplediluents, solvents, stabilizing agents, tensides, sweetening agents,preserving agents and/or flavouring agents.

Where ingredient (b+c) is semi-solid or of high viscosity e.g. as in thecase of MAISINE, the addition of a diluent or solvent to reduceviscosity will be especially advantageous, in particular to improvehandlability of the composition, for example to facilitate filling intocontainers, particularly where these are of small diameter as in thecase of ampoules, capsules and the like. Accordingly in a furtherembodiment the present invention also provides:

B⁴ A pharmaceutical composition as defined under any one of B¹ to B³above additionally comprising:

d) a solvent or diluent miscible with (b+c) and reducing, or capable ofreducing, the viscosity of (b+c).

When present, component (d) suitably comprises a trans-esterificationproduct of a natural vegetable oil triglyceride and a polyalkylenepolyol. Such trans-esterification products are known from the art andmay be obtained e.g. in accordance with the general procedures describedin U.S. Pat. No. 3,288,824. They include transesterification products ofvarious natural (e.g. non-hydrogenated) vegetable oils for example,maize oil, kernel oil, almond oil, ground nut oil, olive oil and palmoil and mixtures thereof with polyethylene glycols, in particularpolyethylene glycols having an average molecular weight of from 200 to800. Preferred components (d) are trans-esterification products obtainedfrom maize oil. Further preferred as (d) are products obtained bytrans-esterification product of the class defined are commerciallyavailable from Etablissement Gattefosse, Boulogne sur Seine, Franceunder the trade name LABRAFIL [see Fiedler, loc. cit., page 539]. Apreferred component (d) is the product LABRAFIL M 2125 CS, apolyoxyethylated, maize oil having an acid no. =ca. 2, a saponificationno. =ca. 155-175 and an iodine no. =ca. 90-100.

Use of LABRAFIL as component (d) is especially indicated where thecompositions of the invention are to be filled into ampoules or the likefor use as the base for a "drink solution" e.g. as hereinafterdescribed.

Further, especially advantageous components (d) are (additional)components (c) as defined under A above, in particular mono- anddi-glycerides, e.g. comprising an esterification product of caprylic andcaptic acid with glycerol. Use of such components (c) as (d) providescompositions in accordance with the invention conforming with theinvention as hereinafter defined under C.

Examples of suitable components (c) for use as (d) include any of thosedescribed under (c.1) to (c.6) below. Especially preferred components(c) for use as (d) comprise products obtained by esterification of fromabout 50 to 75, e.g. about 60, parts by weight of capric acid withglycerol, and comprising, or consisting mainly or essentially ofcaprylic/capric acid mono- and di-glycerides. Especially preferredproducts of this class are those available under the trade name IMWITORas described under (c.1) below, in particular the product IMWITOR 742.

A further possible, though less preferred, component (d) is ethanol,e.g. absolute ethanol.

In addition it has also been found that the bio-availability of thecompositions in accordance with B¹ to B³ above may be further increasedif they additionally comprise an emulsifying agent. Accordingly, in yeta further embodiment, the present invention additionally provides:

B⁵ A pharmaceutical composition as defined under any one of B¹ to B⁴above additionally comprising:

e) an emulsifying agent.

Components (e) may or may not be directly miscible (e.g. capable offorming a solution, suspension or the like) with other componentspresent in the compositions defined, e.g. components (a) and (b+c).Where components (e) are non-miscible, the compositions of the inventionwill be bi-phasic, i.e. comprise at least a double-system e.g. withcomponents (a) and (b+c) and, optionally, (d) comprised in a first layeror phase of the composition and component (e) comprised in a second,separate layer, or phase above or below the said first layer or phase(depending on the relative specific gravity of the two layers orphases). Such bi-phasic compositions are also to be understood as beingwithin the purview of the present invention. Where the compositions ofthe invention are bi-phasic, separate phases may be commingled prior toadministration, e.g. by shaking, stirring or other agitation, or may becontained together within a single unit dosage form, e.g. capsule or thelike, so as to permit concommitant administration and release within thegastro-intestinal tract.

Component (e), when present, preferably comprises a tenside having ahydrophilic-lipophilic balance (HLB) of at least 10. Examples ofsuitable components (e) include any of those described under (e'.1) to(e'.8) below, in particular under (e'.1), most especially those knownand commercially available under the trade name CREMOPHORE, for exampleCREMOPHORE RH40.

In the compositions of the invention in accordance with B¹ to B⁵ above,(a) is suitably present in an amount of from about 2.0 to about 20%,preferably from about 5 to 15%, most preferably about 10% by weight,based on the total weight of the composition. Accordingly, when (b+c) ispresent alone, this will generally be present in an amount of from about80 to about 98%, preferably from about 75 to about 95%, most preferablyabout 90% based on the total weight of the composition.

When (d) is present and is a trans-esterification product of a naturalvegetable oil triglyceride and a polyalkylene polyol (for example aLABRAFIL), (d) is suitably present in an amount of up to about 50%,preferably from about 20 to about 40%, most preferably about 30%, basedon the total weight of the composition.

When (d) is present and is an esterification product of caprylic andcaproic acid with glycerol (for example an IMWITOR), (d) is suitablypresent in an amount of up to 40%, preferably in an amount of from about2 to about 40%, most preferably in an amount of from about 2 to about20% based on the total weight of the composition.

When (d) is present and is ethanol, (d) is suitably present in an amountof up to about 10%, preferably in an amount of about 2-5% based on thetotal weight of the composition.

When present, (e) is suitably present in an amount of up to 10%,preferably about 5% (e.g. ca. 6%), based on the total weight of thecomposition.

When present, components (d) and/or (e) will generally be introduced inpartial replacement of component/ingredient (b+c). Thus where thecompositions of the invention comprise (a)+(b+c)+(e) [but not (d)] and(e) is present in an amount of 6% by weight based on the total weight ofthe composition, (b+c) will generally be present in an amount of fromabout 74 to about 92%, preferably from about 69 to about 89% mostpreferably about 84% based on the total weight of the composition.

For the purposes of oral administration, the compositions of theinvention in accordance with B¹ to B⁵ above will preferably be put up inunit dosage form. In so far as the compositions are liquid this may bedone by filling into a solid pharmaceutical unit dosage container suchas a capsule, e.g. a hard or soft gelatin capsule, for direct oraladministration or a phial or ampoule, e.g. for subsequent admixture witha drink-mixture, e.g. chocolate drink, prior to administration ascurrently practiced for the known cyclosporin "drink solution". Wherethe compositions of the invention are bi-phasic as hereinbeforedescribed, the components may be homogenised to produce a uniformmixture prior to filling into the chosen dosage form, thus facilitatingthe filling procedure. Component (e) may then separate out from othercomponents present to form a separate phase or layer, e.g. after closureof the unit dosage form. Most preferably the compositions of theinvention are put up in soft gelatin capsule form.

In general: where unit dosage forms, e.g. of the type described above,are desired, components (a) and (b+c) are suitably present in thecompositions of the invention in a ratio of from about 1:4 to about1:50, preferably from about 1:5 to about 1:20, most preferably about 1:9p.p.w. [(a):(b+c)].

When a component (d) is present and this is the trans-esterificationproduct of a natural vegetable oil triglyceride and a polyalkylenepolyol, components (d) and (b+c) are suitably present in a ratio of fromabout 1:1.25 to about 1:3.5, most preferably about 1:2 p.p.w.[(d):(b+c)]. When a component (d) is present and is thetrans-esterification product of a natural vegetable oil triglyceride anda polyalkylene polyol, components (a), (b+c) and (d) are suitablypresent in a ratio of from about 1:9:0.1 to about 1:3.5:5.5, preferablyfrom about 1:7:2 to about 1:5:4, most preferably about 1:6:3 p.p.w.[(a):(b+c):(d)].

When a component (d) is present and this is a component (e) ashereinafter described, especially an esterification product of caprylicand caproic acid with glycerol, components (d) and (b+c) are suitablypresent in a ratio of from 1:50 to about 1:1, preferably from about 1:45to about 1:3.5 p.p.w. [(c):(b+c)]. When a component (d) is present andthis is an esterification product of caprylic and caproic acid withglycerol, components (a), (b+c) and (d) are suitably present in a ratioof from about 1:9:0.2 to about 1:5:4, preferably from about 1:8.8:0.2 toabout 1:7:2 p.p.w. [(a):(b+c):(d)].

When component (d) is present and is ethanol, components (d) and (b+c)are suitably present in a ratio of from about 1:8 to about 1:90preferably from about 1:20 to about 1:45 p.p.w. [(d):(b+c)].

When a component (e) is present, components (a) and (e) are suitablypresent in a ratio of from about 1:0.1 to about 1:5, preferably fromabout 1:0.3 to about 1:1, most preferably about 1:0.5 p.p.w. [(a):(e)].When a component (d) is present, components (a), (b) and (d) aresuitably present in a ratio of from about 1:9:0.1 to about 1:8:1,preferably about 1:8.5:0.5 p.p.w. [(a):(b+c):(d)].

When components (d) and (e) are both present, and (d) is thetrans-esterification product of a natural vegetable oil triglyceride anda polyalkylene polyol, components (a), (b+c), (d) and (e) are suitablypresent in a ratio of from about 1:9:0.1:0.1 to about 1:3:5:1,preferably from about 1:6.5:2:0.5 to about 1:4.5:4:0.5, most preferablyabout 1:5.5:3:0.5 p.p.w. [(a):(b+c):(d):(e)].

In an alternative and specific embodiment, compositions of the inventionin accordance with B¹ to B⁵ above may be put up in unit dosage from bycompounding or admixture with an appropriate pharmaceutically acceptablebase material such that the obtained product or admixture is capable ofbeing formed into a solid unit dosage. In so far as the compositions ofthe invention may themselves be solid or semi-solid, e.g. when (b+c)comprises MAISINE or the like, particularly when (d) is absent, suchproducts and admixtures are readily achievable. Suitable base materialsinclude any of those known and commonly employed in the art andproviding products and admixtures with the compositions of the inventioncapable of being formed, e.g. moulded, pressed, cast or otherwiseshaped, into unit dosage form.

For the preparation of unit dosage forms in this particular manner, thecompositions of the invention preferably comprise components (a) and(b+c) and, optionally (e), but not (d).

In contradistinction to compositions to be contained in an ampoule orthe like, it is further preferred that compositions according to theinvention and processed in this manner comprise components (a) and (b+c)in a ratio of from about 1:1 to about 1:10, preferably from about 1:1 toabout 1:5, most preferably about 1:2.5 p.p.w. [(a):(b+c)].

Preferred base materials for use in accordance with this particularmodification of the present invention comprise in particular naturalfats, especially vegetable fats, for example cacao fat or cacao butterand conventional chocolate bases, e.g. couverture chocolate and mixturesthereof. Where a natural fat is employed the ratio of (a) to fat ispreferably from about 1:0.5 to about 1:2, more preferably from about 1:1to about 1:1.5, most preferably about 1:1.25 p.p.w. [(a):fat]. Where achocolate base is employed the ratio of (a) to chocolate is preferablyfrom about 1:10 to about 1:50, more preferably from about 1:10 to 1:30and most preferably about 1:20 p.p.w. [(a):chocolate]. By compounding oradmixture of a composition in accordance with the invention with a fatand chocolate, e.g. in the above described proportion, a product may beobtained in the form of a substantially homogenous mass which can be putup in unit dosage form, e.g. by pouring as a warm melt into anappropriate mould, e.g. as described in the following example 5, toprovide a cyclosporin sweet meat, bon-bon or candy as unit dosage form.

Alternatively components (a) and (b+c) may be filled, optionallytogether with component (d), into a chocolate mantel, cover or capsule.

Unit dosage forms in accordance with B¹ to B⁵ above suitably containfrom about 25 to 500, more preferably about 50 to 300, especially 50,100, 150 or 200 mg of component (a), e.g. of Ciclosporin, foradministration e.g. 1× or from 2 to 3× daily.

Compositions in accordance with the present invention, e.g. inaccordance with A or any one of B¹ to B⁵ above, which comprise acomponent (e) as hereinbefore set forth, in particular comprising (e') atenside having an HLB of at least 10, are of especial interest. Inparticular such compositions have been found to be surprisingly andunexpectedly well adapted to meet difficulties in the art hithertoencountered in relation to cyclosporin dosaging, e.g. as hereinbeforeparticularly discussed.

Accordingly, in an especially preferred embodiment, the presentinvention further provides:

C. A pharmaceutical composition comprising:

a) a cyclosporin as active ingredient in a carrier medium comprising

b) a fatty acid triglyceride,

c) a glycerol fatty acid partial ester or propylene glycol (e.g.1,2-propylene glycol) or sorbitol complete or partial ester, and

e') a tenside having a hydrophilic-lipophilic balance (HLB) of at least10.

In a series of specific embodiments the present invention also provides:

A composition as defined under C above, which composition:

i) is free or substantially free of ethanol; or

ii) comprises Ciclosporin or [Nva]² -Ciclosporin as component (a); or

iii) comprises components (a) and (e') in a ratio of 1: at least 1p.p.w.

Provisos (i) to (iii) above are not mutually exclusive. Compositions inaccordance with C complying with said provisos and in which components(b) and (c) comprise, or consist or consist essentially of theindividual components of an ingredient or component (b+c) as definedunder any one of B¹ to B³ above, e.g. in which components (b) and (c)consist or consist essentially of the individual components of atrans-esterification product of a vegetable oil with glycerol, are ofparticular interest.

Component (a) is suitably present in the compositions as defined under Cabove in an amount of from ca. 2-20%, more preferably ca. 5-15% based onthe total weight of components (a) to (c) and (e') inclusive. Thepreferred component (a) is Ciclosporin. A further preferred component(a) is [Nva]² -Ciclosporin, also known as cyclosporin G.

Examples of suitable components (e') in the compositions as definedunder C. above are:

e'.1 Reaction products of a natural or hydrogenated castor oil andethylene oxide. Such products may be obtained in known manner, e.g. byreaction of a natural or hydrogenated castor oil with ethylene oxide,e.g. in a molar ratio of from about 1:35 to about 1:60, with optionalremoval of the polyethyleneglycol component from the product, e.g. inaccordance with the methods disclosed in German Auslegeschriften1,182,388 and 1,518,819. Especially suitable are the various liquidtensides available under the trade name CREMOPHOR. Particularly suitableare the products CREMOPHOR RH 40 having a saponification number of ca.50-60, an acid number <1, an iodine number <1, a water content (Fischer)<2%, an n_(p) ⁶⁰ of ca. 1,453-1,457 and an HLB of ca. 14-16; CREMOPHORRH 60 having a saponification number of ca. 40-50, an acid number <1, aniodine number <1, a water content (Fischer) 4.5-5.5%, and an n_(p) ²⁵ ofca. 1.453-1.457 and an HLB of ca. 15-17; and CREMOPHOR EL having amolecular weight (by steam osmometry) of ca. 1630, a saponificationnumber of ca. 65-70, an acid number of ca. 2, an iodine number of ca.28-32 and an n_(p) ²⁵ of ca. 1.471. Also suitable for use in thiscategory are the various tensides available under the trade name NIKKOL,e.g. NIKKOL HCO-40 and HCO-60. The said product NIKKOL HCO-60 is areaction product of hydrogenated castor oil and ethylene oxideexhibiting the following characteristics: acid value ca. 0.3;saponification number of ca. 47.4; hydroxy value of ca. 42.5; pH (5%) ofca. 4.6; color APHA=ca. 40; m.p.=ca. 36.0° C.; freezing point=ca. 32.4°C.; H₂ O content (%, KF)=0.03.

e'.2 Polyoxyethylene-sorbitan-fatty acid esters, e.g. mono- andtri-lauryl, palmityl, stearyl and oleyl esters, e.g. of the type knownand commercially available under the trade name TWEEN (c.f. Fiedler,"Lexikon der Hilfstoffe", 2nd revised and expanded edition (1981),Vol.2, p.p. 972-975) including the products TWEEN

20 [polyoxyethylene(20)sorbitanmonolaurate],

40 [polyoxyethylene(20)sorbitanmonopalmitate],

60 [polyoxyethylene(20)sorbitanmonostearate],

65 [polyoxyethylene(20)sorbitantristearate],

85 [polyoxyethylene(20)sorbitantrioleate],

21 [polyoxyethylene(4)sorbitanmonolaurate],

81 [polyoxyethylene(5)sorbitanmonooleate].

Especially preferred products of this class for use in the compositionsof the invention are the above products TWEEN 40 and TWEEN 80.

e'.3 Polyoxyethylene fatty acid esters, for example polyoxy- ethylenestearic acid esters of the type known and commercially available underthe trade name MYRJ (c.f. Fiedler, loc. cit., 1, p.228); an especiallypreferred product of this class for use in the compositions of theinvention is the product MYRJ 52 having a D²⁵ =ca. 1.1., m.p.=ca.40°-44° C., an HLB value=ca. 16.9., an acid value=ca. 0-1 and asaponification no. =ca. 25-35.

e'.4 Polyoxyethylene-polyoxypropylene co-polymers and block co-polymers,e.g. of the type known and commercially available under the trade namesPLURONIC, EMKALYX and POLOXAMER (c.f. Fiedler, loc. cit., 2, p.p.720-723). An especially preferred product of this class for use in thecompositions of the invention is the product PLURONIC F68, having anm.p.=ca. 52° C. and a molecular weight of ca. 6800-8975. A furtherpreferred product of this class for use in the compositions of theinvention is the product POLOXAMER 188.

e'.5 Dioctylsuccinate or di-[2-ethylhexyl]-succinate (c.f. Fiedler, loc.cit., 1, p.p. 307).

e'.6 Phospholipids, in particular lecithins (c.f. Fiedler, loc. cit., 2,p.p. 559-560). Lecithins suitable for use in the compositions of theinvention include, in particular, soya bean lecithins.

e'.7 Propylene glycol mono- and di-fatty acid esters such as propyleneglycol dicaprylate (also known and commercially available under thetrade name MIGLYOL 840), propylene glycol dilaurate, propylene glycolhydroxystearate, propylene glycol isostearate, propylene glycol laurate,propylene glycol ricinoleate, propylene glycol stearate and so forth(c.f. Fiedler, loc. cit., 2, p.p. 760 et seq.).

e'.8 Sodium lauryl sulfate.

The ratio of components (a):(e') in the compositions in accordance withC. above is suitably of the order of 1:1 to 25 p.p.w., more preferably1:1.25 to 20 p.p.w., yet more preferably 1:1.5 to 8 or 10 p.p.w, e.g.ca. 1:2 to 5 p.p.w.. Most preferably the ratio of components (a):(e') is1: at least 2 p.p.w. Component (a) is thus suitably present in thecompositions of the invention in an amount e.g. of from ca. 20-50%, morepreferably 25-40%, by weight based on the total weight of components (a)and (e').

Components (b) and (c) in compositions in accordance with C. above maycomprise or consist or consist essentially of the individual components(b) and (c) of a single ingredient, e.g. single material or product.Examples of ingredients comprising both components (a) and (b) suitablefor use in the present invention include for example known mixed fattyacid tri-glyceride and fatty acid mono-/di-glyceride products. Suitableproducts of this type include, in particular, transesterificationproducts of vegetable oils with glycerol, propylene glycol (e.g.1,2-propylene glycol) or sorbitol e.g. as hereinbefore described inrelation to definitions B¹ to B³ above.

Suitable components of this type thus include any ingredient (b+c) ashereinbefore described, in particular products of the type MAISINE andSORBITO GLYCERIDES.

In the case of compositions in accordance with C. above of which thecomponents (b) and (c) consist or consist essentially of the individualcomponents (b) and (c) of a single ingredient, e.g. of which thecomponents (b) and (c) are comprised entirely or substantially entirelyof trans-esterification products as hereinbefore described above, theratio of (a):(b+c) is suitably of the order of 1:0.75-35, preferably1:1-25 p.p.w., more preferably the ratio is of the order of 1:3-10,especially ca. 1:6 p.p.w.. Where only ingredients comprising both (b)and (c) are employed, (b+c) are thus suitably present in thecompositions of the invention in an amount of from ca. 15-70%, morepreferably ca. 20-50% by weight, based on the total weight of components(a) to (c) and (e') inclusive.

To enable combination of components (b) and (c) in the compositions ofthe invention, e.g. as defined under C. above, in preferred proportionas hereinafter described, component (b) in the compositions of theinvention will however preferably comprise at least one ingredientdefinable as a fatty acid triglyceride as such, e.g. material orproduct, which is, or which consists or consists essentially ofcomponents (b) as hereinbefore defined (i.e. fatty acid triglycerides),e.g. which comprises at least 75%, preferably at least 90%, morepreferably at least 95% by weight of components (b). Component (c) inthe compositions of the invention will also preferably comprise at leastone ingredient which is definable as a glycerol fatty acid partial esteror propylene glycol or sorbitol complete or partial ester as such, e.g.which is or which consists or consists essentially of components (c) ashereinbefore defined, e.g. which comprises at least 75%, preferably atleast 90%, more preferably at least 95% by weight of said components(c).

More preferably components (b) and (c) in the compositions of theinvention, e.g. as defined under c. above, will comprise separateingredients combinable in selected proportion [(b):(c)] as hereinafterdescribed. With respect to the components (b) and (c), the compositionsof the invention will thus most preferably comprise a bi-partitecombination of ingredients complying with definition (b) and ofingredients complying with definition (c), e.g. a combination of a firstingredient or ingredients consisting or consisting essentially ofcomponents (b) and of a second ingredient or ingredients consisting orconsisting essentially of components (c).

Suitable components (b) include both saturated (including hydrogenated)and unsaturated fatty acid tri-glycerides, in particular animal orvegetable oils. The fatty acid constituents of components (b) suitablyinclude, saturated or mono-, di- or poly-unsaturated acids having e.g.chain lengths of from 6 to 22 carbon atoms. Especially suitable for usein accordance with the invention are fatty acid triglycerides having ahigh content of unsaturated fatty acid constituents in particular mono-,di- and poly-unsaturated fatty acids having at least 16 carbon atoms,preferably 18 carbon atoms or more, in particular having a high oleic,linoleic or linolenic fatty acid constituent content. Of particularinterest are fatty acid triglycerides having a linoleic and/or linolenicacid constituent content of at least 45%, preferably at least 60% and upto 65 or 80%, e.g. where super-refined oils are used.

A first group of fatty acid triglycerides suitable for use in accordancewith the invention includes saturated C₆₋₁₂ fatty acid vegetable oiltriglycerides, e.g. caprylic-capric acid triglycerides. Examples ofingredients suitable as components (b) thus include fractionatedvegetable oils, e.g. fractionated coconut oils such as are known andcommercially available under the trade name MIGLYOL (c.f. Fiedler, loc.cit., 2, 615 and 616), including MIGLYOL 810, a fractionated coconutoil, caprylic-capric acid triglyceride having a molecular weight of ca.520 and a fatty acid constitution=C₆ max. ca. 2%, C₈ ca. 65-75%, C₁₀ ca.25-35%, C₁₂ max. ca. 2%. MIGLYOL 810 has the following further physicalcharacteristics: α_(D) ²⁰ =1-4490-1.4510, acid no.=max. 0.1,saponification no.=ca. 340-360, iodine value=max. 1. Especiallypreferred is MIGLYOL 812, a fractionated coconut oil, caprylic-capricacid triglyceride having a molecular weight of ca. 520, and a fatty acidconstitution=C₆, max. ca. 3%, C8 ca. 50-65%, C₁₀ ca. 35-40%, C₁₂ max.ca. 5%. MIGLYOL 812 has the following further physical characteristics:α_(D) ²⁰ =1.4480-1.4500, Saponification no.=ca. 330-345, iodinevalue=max. 1.

Further ingredients of similar class suitable for use as components (b)include those known and commercially available under the trade nameESTASAN, for example ESTASAN GT 8-60 and GT 8-65. ESTASAN GT 8-60 is avegetable oil fatty acid triglyceride in which the fatty acid componentsare comprised chiefly of saturated C₈₋₁₀ fatty acids, in particularcaprylic and capric acids. Fatty acid constitution=caproic (Ca) max. ca.3%, caprylic (C₈) max. ca. 50-65%, capric (C₁₀) max. ca. 35-45%, lauric(C₁₂) max. ca. 3%. ESTASAN GT 8-60 exhibits the following additionalphysical characteristics: saponification no.=ca. 325-345, iodineno.=max. ca. 1, acid value=max. ca. 0.1, α_(D) ²⁰ =ca. 1.448-1.451.ESTASAN GT 8-65 is also a vegetable oil fatty acid triglyceride,comprised chiefly of saturated C₈₋₁₀ fatty acids, in particular caprylicand capric acids. Fatty acid constitution=caproic max. ca. 1%, caprylicmin. ca. 65%, capric ca. 25-35%, lauric max. ca. 1%.

Yet further ingredients of this class are those known and commerciallyavailable under the trade name MYRITOL, for example MYRITOL 318 [c.f.Fiedler, loc. cit., 2, p.p. 635-636]. MYRITOL 318 is a caprylic/capricacid triglyceride having a saponification no.=ca. 340-350, an iodineno.=ca. 0.5 and an n_(D) ²⁰ =ca. 1.448-1.450.

Further ingredients suitable for use as components (b) include, e.g.vegetable oils such as corn oils, almond oils, kernel oils (for exampleapricot kernel oils), avocado oils, babassu oils, higher fatty acidcoconut oils, primrose oils, grapeseed oils, menhaden oils, olive oils,orange roughy oils, peanut oils, safflower oils, sesame oils, soybeanoils and wheat-germ oils as well as animal oils such as fish oils, e.g.fish liver oils, for example shark oils, and mink oils. Refined oils ofany of the above types are of particular interest for use in accordancewith the present invention, in particular refined plant oils, e.g.having the following approximate oleic/linoleic/linolenic acidconstituent content:

    ______________________________________                                                  LINOLEIC   LINOLENIC                                                OLEIC ACID                                                                              ACID       ACID       EXAMPLE                                       ______________________________________                                        ca. 9%    ca. 68%    ca. 15%    evening primrose                              ca. 27%   ca. 64%    --         grapeseed                                     ca. 4%    ca. 13%    ca. 76%    safflower                                     ca. 5%    ca. 40%    ca. 47%    sesame                                        ca. 25%   ca. 54%    ca. 6%     soybean                                       ca. 14%   ca. 58%    ca. 8%     wheat-germ                                    ______________________________________                                    

Component (c) for use in compositions of the invention, e.g. as definedunder C. above, suitably comprises a glycerol fatty acid partial ester,i.e. a fatty acid mono- or di-glyceride, or acetylated derivativethereof. Ingredients suitable for use as component (c) will preferablybe free or substantially free of any fatty acid tri-glyceride component,e.g. contain less than 25%, preferably less than 10%, more preferablyless than 5%, e.g. less than 1 or 2% fatty acid triglycerides.

Components (c) as aforesaid include both symmetric mono- anddi-glycerides (i.e. β-monoglycerides and α,α¹ -diglycerides) as well asasymmetric mono- and di-glycerides (i.e. α-monoglycerides andα,β-diglycerides) and acetylated derivatives thereof. They also includeboth uniform glycerides (i.e. in which the fatty acid constituent iscomposed primarily of a single fatty acid) as well as mixed glycerides(i.e. in which the fatty acid constituent is composed of various fattyacids) and acetylated derivatives thereof.

The fatty acid constituent of components (c) may include both saturatedand unsaturated fatty acids having a chain length of from 6 to 22 carbonatoms. Preferably the fatty acid constituent will predominantly comprisesaturated or unsaturated fatty acids having a chain length of from 8 to18 carbon atoms, in particular 8, 10 or 14 to 18, e.g. 16 or 18 carbonatoms. Especially suitable are mono- and di-glycerides in which thefatty acid constituent is comprised predominantly of one or more membersselected from the group consisting of caprylic, capric, linolenic,palmitic, stearic and oleic acids.

Particularly preferred for use as components (c) are ingredientscomprising mono- and di-glycerides, wherein the mono-/di-glyceridecontent is at least 50%, preferably at least 60%, more preferably atleast 75% by weight, and acetylated derivatives thereof. Examples ofappropriate ingredients for use as components (c) are:

c.1 Fatty acid mono- and di-glycerides, e.g. products obtained orobtainable by esterification of from about 50 to 75, e.g. about 60,parts by weight, and from about 50 to about 25, e.g. about 40, parts byweight of capric acid with glycerol, and comprising, or consistingmainly or essentially of caprylic/capric acid mono- and di-glycerides.Examples of such products include those known and commercially availableunder the trade name IMWITOR (c.f. Fiedler, loc. cit., 1, p. 491), inparticular: caprylic and capric acid mono- and di-glycerides such asIMWITOR 742. IMWITOR 742 is the esterification product of a mixture ofca. 60 p.p.w. caprylic acid and ca. 40 p.p.w. capric acid with glycerol.It comprises ca. 40 to 50% or more mono-glycerides. It is a yellowishcrystalline mass, liquid at ca. 26° C. It exhibits the following,additional characterising data--acid value=max. ca. 2%, iodinevalue=max. ca. 1.0, saponification no.=ca. 250-280, free glycerolcontent=max. ca. 2%, unsaponifiables=0.3% max., peroxide no.=max 1; andstearic acid mono-glycerides such as IMWITOR 191, which comprises atleast 90% mono-glycerides as aforesaid and exhibits the following,additional characterising data--m.p.=ca. 63°-66° C., acid value=max. ca.3, saponification no.=ca. 160-170, iodine value=max. ca. 3, freeglycerol content=max. ca. 2%, and IMWITOR 960K which comprises 30-40%monoglycerides as aforesaid and exhibits the following, additionalcharacterising data--m.p. rising from ca. 56 to ca. 60° C.,saponification no.=ca. 155-170, acid value=max. ca. 3, iodine value=max.ca. 3, free glycerol content=max. ca. 4%.

c.2 Fatty acid mono- and di-glycerides as commercially available underthe trade name CUTINA (c.f. Fiedler, loc. cit., 1, p.p. 263 and 264): inparticular palmitic and stearic acid mono- and di-glycerides such asCUTINA MD-A, which comprises mono- and di-glycerides as aforesaid andexhibits the following characterising data - acid value=max. ca. 8,saponification no.=ca. 160-170; and stearic acid mono-glycerides such asCUTINA GMS which comprises mono-glycerides as aforesaid and exhibits thefollowing characterising data--m.p.=ca. 54°-60° C., acid value=max. ca.2, saponification no=ca. 162-173, iodine value=max. ca. 2.

c.3 Fatty acid mono-glycerides as commercially available under the tradename MYVEROL (c.f. Fiedler, loc. cit., 2, 637), in particular C₁₈ fattyacid, e.g. linolenic acid, mono-glycerides such as MYVEROL 18-92, whichcomprises at least 90% mono-glycerides as aforesaid and exhibits thefollowing additional characterising data: acid value=max. ca. 3.0,diglyceride content=max. ca. 5%, free glycerol content=max. ca. 1.2%.

c.4 Fatty acid mono-glycerides as commercially available under the tradename MYVAPLEX (c.f. Fiedler, loc. cit., 2, 637), in particular stearicacid mono-glycerides such as those of the MYVAPLEX 600 series, e.g.MYVAPLEX 600P which comprises ca. 94-90% mono-glycerides as aforesaidand exhibits the following additional characterising data--m.p.=ca. 73°C., density=ca. 0.92 g/cm³ at 80° C.

c.5 Fatty acid mono-glycerides as commercially available under the tradename ESTAGEL, for example ESTAGEL G-18 which is comprised primarily ofC₁₆₋₁₈ fatty acid mono-glycerides in particular palmitic and stearicacid mono-glycerides. The α-monoglyceride content of Estagel G-18 ismin. ca. 40%. Further characterising data: acid value=max. ca. 2,saponification no.=ca. 162-173, iodine no.=max. ca. 3, free glycerolcontent=max. ca. 6%.

c.6 Acetylated fatty acid mono- and di-glycerides such as commerciallyavailable under the trade name MYVACET (c.f. Fiedler, loc. cit.,2, p.p.636-637), in particular mono- and di-acetylated fatty acidmono-glycerides, for example mono- and di-acetylated stearic acidmono-glycerides such as: MYVACET 9-40 which has the followingcharacterising data--α_(D) ⁵⁰ =ca. 1.4468-1.4476, m.p.=ca. 5° C., acidvalue=max. ca. 1.5, saponification no.=ca. 375-385; and MYVACET 9-45which has the following characterising data--αD⁵⁰ =Ca. 1.4465-1.4475,m.p.=ca. 8°-12.4° C., acid value=ca. 1.5, saponification no.=ca.375-385.

Further components (c) which are of particular utility, are mixedglycerol fatty acid partial esters and propylene glycol complete andpartial esters, e.g. products comprising fatty acid mono- anddi-glycerides and propylene glycol fatty acid mono- and di-esters.Examples of such components (c) include:

c.7 Fatty acid mono- and di-glycerides/propylene glycol fatty acid mono-and di-esters as commercially available under the trade name ATMOS [c.f.Fiedler, loc. cit., 1, p. 156], in particular ATMOS 300 in which thefatty acid moieties are comprised principally of oleic acid residues andATMOS 150 in which the fatty acid moleties are comprised principally ofstearic acid residues.

c.8 Fatty acid mono- and di-glycerides/propylene glycol fatty acid mono-and di-esters as commercially available under the trade name ARLACEL[c.f. Fiedler, loc. cit., 1, p.p. 143-144] in particular ARLACEL 186 inwhich the fatty acid moieties are comprised principally of oleic acidresidues.

Components (b) and (c) are preferably present in the compositions of theinvention, e.g. as defined under C. above, in a ratio of about 0.02 to3.0 p.p.w. More preferably the ratio of components (b):(c) is of theorder of 1:0.1 to 2.5 p.p.w., most preferably 1:0.25-1.25 p.p.w. Whencomponents (b) and (c) in the compositions of the invention, e.g.compositions C, comprise separate ingredients, e.g. as described above,the said ingredients will thus suitably be employed in the same relativeratios. The amount of components (b) in the compositions of theinvention as defined under C. above is thus suitably of the order offrom 10-50%, preferably 20-40% by weight, based on the total weight ofcomponents (a) to (c) and (e') inclusive, and the amount of components(c) in said compositions is suitably of the order of from 1-30%,preferably 10-25% by weight, based on the total weight of components (a)to (c) and (e') inclusive.

The ratio of components (a):(b) plus (c) in the compositions of theinvention, e.g. as defined under C, is suitably of the order of 1:0.5 to40 p.p.w. Preferably, the ratio of (a):(b) plus (c) is about 1:1 to 35,more preferably about 1:1.5 to 30 p.p.w., most preferably about 1:2 to6.

In accordance with the foregoing the present invention also provides

D. A pharmaceutical composition as defined under C above comprising atleast one ingredient which consists or consists essentially of, acomponent or components as defined under (b) above;

E. A pharmaceutical composition as defined under C above comprising atleast one ingredient which consists or consists essentially of acomponent or components as defined under (c) above;

F. A pharmaceutical composition as defined under C above in whichcomponents (a) and (b) comprise separate ingredients.

The compositions of the invention, e.g. as defined under any of C to Fabove, may include further components, for example thickening agents,granulating agents, dispersing agents, flavouring and/or colouringagents or anti-microbial agents etc. . . . as required. They may alsoinclude polymeric thickening agents to permit processing into a solid orsemi-solid mass suitable for tabletting or forming into granules.

The compositions of the invention, in particular as defined under any ofC to F above, will suitably include anti-oxidants to improve shelf-life,for example butyl-hydroxy-toluene (or BHT), butyl-hydroxy-anisole (orBHA), ascorbyl palmirate, ascorbic acid, citric acid orα-tocopherol-acetate.

In particular the compositions of the invention will suitably compriseone or more stabilizors or buffering agents, e.g. to prevent degradationof component (a) during processing or on storage. Such stabilizors mayinclude acid stabilizors such as citric acid, acetic acid, tartaric acidor fumaric acid as well as basic stabilizors such as potassium hydrogenphosphate, glycine, lysine, arginine or tris(hydroxymethyl)aminomethane.

Such stabilizors or buffer agents will appropriately be added in anamount sufficient to achieve or maintain a pH within the range of fromabout 5 to 7, more preferably between 6 and 7.

When components (b) and (c) in the compositions of the invention arecomprised of a single ingredient which is the trans-esterificationproduct of a vegetable oil with glycerol, the compositions of theinvention will preferably be subject to proviso (i) as set forth underC. above, i.e. they will be free or substantially free of ethanol.Suitably they will be free or substantially free of any furthercomponent serving as a diluent or as a solvent medium for component (a),e.g. free of any such diluent or solvent other than a component (b), (c)or (b+c) as hereinbefore described.

While proviso (i) is applied above in a specific instance, compositionsin accordance with the invention which are free or substantially free ofethanol are in general preferred. Compositions in accordance with theinvention which are free or substantially free of any further componentserving as a diluent or as solvent medium for (a), are also, in general,preferred. In a yet further series of embodiments the present inventionthus also provides:

G. A pharmaceutical composition as defined under any one of (A) to (F)above which is free, or substantially free, of ethanol; and

H. A pharmaceutical composition as defined under any one of (A) to (F)above which is free or substantially free of any further componentserving as a diluent or as solvent medium for component (a).

Compositions as aforesaid suitably comprise less than 2%, more suitablyfrom 0 to 0.5 or 1% by weight ethanol, based on the total weight of thecomponent ingredients. Compositions as aforesaid suitably comprise lessthan 20%, more preferably less than 10%, e.g. from 0 to 2.5 or 5.0% byweight further components serving as diluent or as solvent medium forcomponent (a). Specific compositions in accordance with the presentinvention are pharmaceutical compositions as defined under any one of A.to H. above consisting, or consisting essentially, of components (b),(c) and (e)/(e') as carrier medium for (a), i.e. exclusive of anythickening, granulating, dispersing, flavouring, colouring, stabilizingagents or the like excipients that may also be present, and which arepresent as additives to the carrier medium.

By components serving as diluents are in particular to be understood,components serving to reduce the viscosity/increase the fluidity of thecompositions of the invention. By components serving as solvent mediumfor (a) are in particular to be understood co-solvents or othermaterials which enhance the solubility of components (a) in thecompositions of the invention. Examples of such components are, inparticular, solvent or diluent components having an HLB of less than 10,for example, trans-esterification products of natural vegetable oiltriglycerides and polyalkylene polyols such as known and commerciallyavailable under the trade name LABRAFIL and ethanol.

Compositions in accordance with the invention may be applied in dosageform suitable for administration by any appropriate means, e.g. in theform of creams, gels or the like for topical or occular administration,or in the form of granules, tablets, capsules, drink-solutions or thelike for oral administration or in a form suitable for intra-lesionalapplication, e.g. in the treatment of psoriasis. Preferably however thecompositions of the invention will be administered orally. In apreferred embodiment the invention accordingly provides a composition ashereinbefore defined in a form appropriate or adapted for oraladministration, in particular in oral unit dosage form. Especiallysuitable unit dosage forms for oral administration include encapsulatedforms, e.g. soft or hard gelatin encapsulated forms.

Oral unit dosage forms in accordance with the invention, in particularin accordance with any of definitions C to F above, will suitablycomprise from 5 to 200 mg, more preferably from 20 to 100 mg, e.g. ca.25, 50 or 100 mg component (a), e.g. for administration 2-5× daily.

In addition to the foregoing the present invention also provides aprocess for the production of pharmaceutical compositions as hereinabovedefined and described which process comprises intimately admixingcomponents (a), (b), (c) or (b+c) and, when present, (d) and/or (e)/(e')thereof.

In a preferred aspect the present invention provides a process asaforesaid, which process comprises intimately admixing a component (a)with a first ingredient (b) which consists or consists essentially ofone or more fatty acid triglycerides and a second ingredient (c) whichcomprises a glycerol fatty acid partial ester or propylene glycol orsorbitol complete or partial ester, or with a first ingredient (b) whichcomprises a fatty acid triglyceride and a second ingredient (c) whichconsists or consists essentially of one or more glycerol fatty acidpartial esters and/or propylene glycol and/or sorbitol complete orpartial esters, and with (e') a tenside having a hydrophilic-lipophilicbalance of at least 10.

In a more preferred aspect the present invention provides a process asaforesaid, which process comprises intimately admixing a component (a)with a first ingredient (b) which consists or consists essentially ofone or more fatty acid triglycerides, a second ingredient (c) whichconsists or consists essentially of one or more glycerol fatty acidpartial esters and/or propylene glycol and/or sorbitol complete orpartial esters, and (e') a tenside having a hydrophilic-lipophilicbalance of at least 10.

The following examples are illustrative of the manufacture ofcompositions in accordance with the present invention:

EXAMPLE 1

A composition is prepared by intimate admixture of the followingcomponents in the indicated relative amounts.

    ______________________________________                                               COMPONENT     AMOUNT                                                   ______________________________________                                        a)       Ciclosporin     100 mg (= ca. 10.5%)                                 b + c)   MAISINE         550 mg (= ca. 57.8%)                                 d)       LABRAFIL M 2125 300 mg (= ca. 33.5%)                                          TOTAL           950 mg                                               ______________________________________                                    

The components are thouroughly admixed in conventional manner and theobtained mixture filled into standard soft gelatin capsules containing950 mg composition per capsule.

EXAMPLE 2

Example 1 is repeated but using the following components in theindicated relative amounts:

    ______________________________________                                        COMPONENT           AMOUNT                                                    ______________________________________                                        a)     Ciclosporin      100 mg (= ca. 10.5%)                                  b + c) MAISINE          490 mg (= ca. 52%)                                    d)     LABRAFIL M 2125  300 mg (= ca. 31.5%)                                  e')    CREMOPHORE RH40   60 mg (= ca. 6.3%)                                          TOTAL            950 mg                                                ______________________________________                                    

The composition is filled into soft gelatin capsules containing 950 mgcomposition/capsule. Subsequent to sealing component (d) separates outfrom other components present.

EXAMPLE 3

Example 1 is repeated but using the following components in theindicated relative amounts:

    ______________________________________                                                COMPONENT   AMOUNT                                                    ______________________________________                                        a)        Ciclosporin   100 mg (= ca. 10.5%)                                  b + c)    MAISINE       850 mg (= ca. 89.5%)                                  ______________________________________                                    

The composition is filled into soft gelatin capsules containing 950 mgcomposition/capsule.

EXAMPLE 4

Example 1 is repeated but using the following components in theindicated relative percentages.

    ______________________________________                                        COMPONENT                  %                                                  ______________________________________                                        a)     (Dihydro-MeBmt).sup.1 -(Val).sup.2 -Ciclosporin                                                       15-25%                                                (also known as dihydrocyclosporin D)                                   b + c) MAISINE                 40-60%                                         c)     IMWITOR 742             10-40%                                         d)     Ethanol                 2-5%                                           ______________________________________                                         (IMWITOR 742 = a glycerine ester available from Dynamite Nobel AG,            TroisdorfObelar, SN).                                                    

The quantity of a) required for a single dosage (ca. 100-200 mg) isdissolved in the remaining components using conventional techniques togive a solution for filling into a soft gelatin capsule.

EXAMPLE 5

    ______________________________________                                        COMPONENT                QANTITY (g)                                          ______________________________________                                        a)    Ciclosporin +          4.0                                                    7% excess              0.028                                                                         4.028                                            b + c)                                                                              MAISINE                10.0                                             x)    Cacao fat              5.0                                              y)    Chocolate base (couverture chocolate)                                                                80.97                                                  Total                  99.998                                           ______________________________________                                    

Components (x) and (y) are mixed thoroughly on a water bath at 40° C.Component (a) is dissolved in component (b+c) under a nitrogenatmosphere and the obtained mixture added to the mixture of (x)+(y). Thewhole is mixed thoroughly on a water bath at 40° C. and then filled intomoulds in 2,500 mg portions, each portion containing 150 mg cyclosporinA. The moulds are stored overnight in a refrigerator and the obtainedunit dosage forms sealed in individual plastic sachets.

EXAMPLE 6

    ______________________________________                                        INGREDIENT           QUANTITY (mg)                                            ______________________________________                                        a)    Cyclosporin (e.g. Ciclosporin)                                                                   50.00                                                b)    MIGLYOL 812        100.00                                               c)    MYVEROL 18-92      100.00                                               e')   CREMOPHORE RH 40   50.00                                                ______________________________________                                    

(a)-(e') are intimately admixed in the indicated proportions inconventional manner and the obtained mixture filled into soft or hardgelatin capsules each containing 50 mg Cyclosporin.

EXAMPLE 7

Soft or hard gelatine capsules each comprising the following indicatedingredients in the indicated amounts, are prepared analogously toExample 1:

    ______________________________________                                                                 QUANTITY                                             INGREDIENT               (mg)                                                 ______________________________________                                        7a   a)       Cyclosporin (e.g. Ciclosporin)                                                                   50.00                                             b)       MIGLYOL 812        100.00                                            c)       IMWITOR 742        100.00                                            e')      CREMOPHORE RH 40   100.00                                       7b   a)       Cyclosporin (e.g. Ciclosporin)                                                                   50.00                                             b + c)   MAISINE            300.00                                            e')      CREMOPHORE RH 40   100.00                                       7c   a)       Cyclosporin (e.g. Ciclosporin)                                                                   50.00                                             b)       Soyabean oil       150.00                                            c)       MYVEROL 18-92      50.00                                             e')      EMULGIN R040*      250.00                                       7d   a)       Cyclosporin (e.g. Ciclosporin)                                                                   50.00                                             b)       Sesame oils        150.00                                            c)       Imwitor 900K       125.00                                            e')      EMULPHOR EL-719*   150.00                                       7e   a)       Cyclosporin (e.g. Ciclosporin)                                                                   50.00                                             b)       MYRITOL 318        75.00                                             c)       ESTAGEL G-18       100.00                                            e')      PLURONIC F68       175.00                                       7f   a)       Cyclosporin (e.g. Ciclosporin)                                                                   50.00                                             b)       ESTASAN GT 8-60    130.00                                            c)       ARLACEL 186        75.00                                             e')      TWEEN 80           125.00                                       7g   a)       Cyclosporin (e.g. Ciclosporin)                                                                   50.00                                             b) + c)  MAISINE            100.00                                            c)       MYVEROL 18-92      200.00                                            e')      CREMOPHORE RH40    100.00                                       7h   a)       Cyclosporin (e.g. Ciclosporin)                                                                   50.00                                             b)       MIGLYOL 812        100.00                                            c)       MYVEROL 18-92      200.00                                            e')      CREMOPHORE RH40    100.00                                       ______________________________________                                         [*c.f. Fiedler, loc. cit. 1, p. 344                                      

The compositions obtained in accordance with examples 1 to 7 aresuitable for administration for the prevention of transplant rejectionor in the treatment of auto-immune disease, e.g. on administration offrom 1 to 5 unit dosages, e.g. capsules, daily. Equivalent compositionmay be prepared substituting any other Cyclosporin, e.g. [Nva]²-Ciclosporin, as component (a) in the same or equivalent amount.

Utility of compositions in accordance with the invention may be shown inanimal or clinical trials, for example performed as follows:

BIOAVAILABILITY STUDY FOR COMPOSITIONS IN ACCORDANCE WITH THE INVENTIONIN THE DOG STUDY I

Test Dosage Forms

A. Unit dosages obtained in accordance with the above example 5, eachunit dosage comprising 100 mg Ciclosporin.

B. Hard-gelatin capsules, each capsule containing 50 mg Ciclosporincompounded with 50 mg ethanol, 150 mg LABRAFIL M. 1944 CS and 212.5 mgolive oil (.tbd.currently commercially available Ciclosporin "drinksolution").

Prepartions A and B are administered to male beagle dogs in randomised,cross-over sequence. Both preparations are administered directly intothe oesophagus and swallowed without chewing, and aministration isfollowed by washing out of the oesophagus with 10 ml water delivered asa spray. Preparation A is administered in single dosages. Preparation Bis administered in double dosage (=100 mg cyclosporin A).

2 ml blood samples are taken prior to administration (control) andsubsequent to administration at intervals of 0.5,1,2,3,4,6,7,12,24,31,48 and 72 hours.

Blood samples are frozen at -20° C. immediately after collection andstored for analysis. Assay is effected by standard cyclosporin Aradioimmunoassay technique employing obtained blood samples in 2μaliquots, assay being effected 2×/sample. Standard curves for the assayare prepared for each individual dog. For characterisation of therelease kinetics, average concentration for each sample, standardvariation, average error and overall average concentration arecalculated.

Variance analysis (p=1%) indicates a significance difference inaverage-AUG (area under curve) value between compositions A and B, withbio-availability for composition A being superior of that forcomposition B.

Advantageous bio-availability levels of the same or equivalent order maybe demonstrated in analogous trials to the above employing compositionsof the invention in soft-gelatin capsule form, e.g. compositionsprepared in accordance with the preceeding examples 1 through 4 or 6 or7.

STUDY II

Groups of 8 beagle dogs (male, ca. 11-13 kg) are used. Animals receiveno food within 18 hours of administration of test composition but areallowed free access to water until administration. Test composition isadministered by gavage, followed by 20 ml NaCl 0.9% solution. Theanimals are allowed free access to food and water three hours afteradministration of test composition.

2 ml blood samples (or 5 ml for the blank) are taken from the venasaphena and collected in 5 ml plastic tubes containing EDTA at -15 min.(blank), 30 min., and 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours postadministration. Blood samples are stored at -18° C. pending assay.

Blood samples are analysed by RIA. Areas under the blood drugconcentration versus time curves are calculated by the trapezoidal rule.Analysis of variance is performed with respect to AUC (area undercurve), Cmax (maximum concentation) and Tmax (time of maximum).Calculated average AUC (in ng hr./ml⁻¹) and Cmax (in ng/ml⁻¹) valuesfrom individual trial runs together with calculated variation inresponse between test animals receiving the same test composition (CV),demonstrate high bioavailability (AUC and Cmax.) coupled with relativelylow variability in subject response both for AUC and Cmax forcompositions in accordance with the invention, e.g. in accordance withexample 6 above, as compared e.g. with results for the known SANDIMMUNCYCLOSPORIN A drink solution composition (e.g. as described in relationto the following CLINICAL TRIAL) administered at the same Ciclosporindosage level.

CLINICAL TRIAL

The advantageous properties of the compositions of the invention on oraladministration may also be demonstrated in clinical trials, e.g.performed as follows:

Trial subjects are adult volunteers, e.g. professionally educated malesof from 30 to 55 years. Trial groups suitably comprise 12 subjects.

The following inclusion/exclusion criteria are applied:

Inclusion: Normal screening ECG; normal blood-pressure and heart rate;body weight=50-95 kg.

Exclusion: Clinically significant intercurrent medical condition whichmight interfere with drug absorption, distribution, metabolism,excretion or safety; symptoms of a significant clinical illness in thetwo-week pre-trial period; clinically relevant abnormal laboratoryvalues or electrocardiogram; need for concomitant medication during theentire course of the study; administration of any drug known to have awell-defined potential toxicity to a major organ system within theprevious 3 months; administration of any investigational drug within 6weeks prior to entry into the trial; history of drug or alcohol abuse;loss of 500 ml or more blood within the past 3 month period; adversedrug reaction or hypersensitivity; history of allergy requiring drugtherapy; Hep.-B/HIV-positive.

Complete physical examination and ECG is performed pre- and post-trial.The following parameters are evaluated within 1-month periods pre- andpost-trial:

Blood: - red blood cell count, haemoglobin, hematocrit, erythrocytesedimentation, white blood cell count, smear, platelet count and fastingglucose;

Serum/plasma--total protein and electrophoresis, cholesterol,triglycerides, Na⁺, K⁺, Fe⁺⁺, Ca⁺⁺, Cl⁻ creatinine, urea, uric acid,SGOT, SGPT, alkaline phosphatase, total bilirubin, α-amylase; Urine--pH,microalbumin, glucose, erythrocytes, ketone bodies, sediment.

Creatinine clearance is also determined 1-month prior to trial entry.

Subjects each receive trial compositions in randomised sequence.Compositions are administered orally, once to a total dose of 150 mgcyclosporin, e.g. Ciclosporin, and at least 14 days are allowed betweeneach administration.

Administration is performed in the morning after an overnight fast of 10hrs. with only water allowed. Only caffein-free beverages are permittedwithin the 24 hr. period following administration. Subjects are notallowed to smoke within the 12 hr. period following administration.Subjects receive a standardised lunch 4 hrs. following administration.

Blood samples (2 ml) are taken 1 hr. prior to administration andpost-administration at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6,9, 12, 14, 24, 28 and 32 hrs.. For determination of creatinine 2 mlblood samples are taken immediately prior to administration and at 12,24 and 48 hrs. post-administration. Samples for cyclosporindetermination are collected in two EDTA coated polystyrene tubes (1 mleach) at each time point and are deep frozen at -20° C. after gentleagitation. Cyclosporin is assayed in whole blood using RIA with specificand/or non-specific MAB assay--detection limit in both cases =ca. 10ng/ml.

In trials carried out in accordance with the above protocoll, e.g.comparing the composition of example 6 in hard gelatin encapsulated formwith the current Ciclosporin drink solution (Ciclosporin=50 mg,LABRAFIL=150 mg, ethanol=50 mg, maize oil=213 mg, in soft gelatinencapsulated form: content end weight=463 mg/dosage) as standard,substantially increased bioavailability levels for the example 6composition are recorded in comparison with the standard as reflected inboth AUC (0-32 hrs) and Cmax values established. In addition, comparisonof variation in whole blood Ciclosporin concentration (as determined byspecific monoclonal RIA) with time following single administration oftest compositions to a Ciclosporin dosage of 150 mg, demonstrates markedreduction in variability of response between all subjects receivingcomposition in accordance with example 1 as compared with that for allsubjects receiving the standard composition.

Similar or equivalent results may be obtained following oraladministration of other compositions in accordance with the invention,e.g. as herein described in examples 1 through 5 or 7.

I claim:
 1. A pharmaceutical composition for oral administrationcomprising cyclosporin A as active ingredient in a carrier mediumcomprising a transesterification product of a natural vegetable oil withglycerol, wherein said transesterification product comprises a mixtureof monoglycerides, diglycerides and triglycerides.
 2. The composition ofclaim 1, wherein said vegetable oil is selected from the groupconsisting of corn oil, almond oil, ground-nut oil, olive oil and palmoil.
 3. The composition of claim 2, wherein said vegetable oil is cornoil.
 4. The composition of claim 1, wherein the amount of monoglycerideis 35 to 50% by weight, based on the total weight of saidtransesterification product.
 5. The composition of claim 2, wherein theamount of diglyceride is less than 40% by weight, based on the totalweight of said transesterification product.
 6. The composition of claim1, wherein the amount of triglyceride is less than 10% by weight, basedon the total weight of said transesterification product.
 7. Thecomposition of claim 1, wherein said carrier medium comprises freeglycerol.
 8. The composition of claim 7, wherein the amount of freeglycerol is less than 10%, based on the total weight of saidtransesterification product.
 9. The composition of claim 1, wherein saidcarrier medium further comprises ethanol.
 10. The composition of claim1, wherein said carrier medium further comprises a transesterificationproduct of a natural vegetable oil triglyceride and a polyalkylenepolyol.
 11. The composition of claim 1, wherein said carrier mediumfurther comprises a reaction product of a natural or hydrogenated castoroil and ethylene oxide.
 12. The composition of claim 1, wherein saidcyclosporin A and transesterification product are present in a weightratio of from about 1:4 to about 1:50.
 13. A pharmaceutical compositionfor oral administration comprising cyclosporin A as active ingredient ina carrier medium comprising a transesterification product of a naturalvegetable oil with sorbitol.
 14. The composition of claim 13, whereinsaid vegetable oil is selected from the group consisting of corn oil,almond oil, ground-nut oil, olive oil and palm oil.
 15. The compositionof claim 14, wherein said vegetable oil is corn oil.
 16. The compositionof claim 13, wherein said transesterification product comprises amixture of sorbitol mono-, di-, tri- and tetra-esters.
 17. Thecomposition of claim 13, wherein the carrier medium comprises freesorbitol.
 18. The composition of claim 17, wherein the amount of freesorbitol is less than 10% by weight, based on the total weight of saidtransesterification product.
 19. The composition of claim 13, whereinsaid carrier medium further comprises ethanol.
 20. The composition ofclaim 13, wherein said carrier medium further comprises atransesterification product of a natural vegetable oil triglyceride anda polyalkylene polyol.
 21. The composition of claim 13, wherein saidcarrier medium further comprises a reaction product of a natural orhydrogenated castor oil and ethylene oxide.
 22. The composition of claim13, wherein said cyclosporin A and transesterification product arepresent in a weight ratio of from about 1:4 to about 1:50.